Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity.

Cortés M, Georgopoulos K - J. Exp. Med. (2004)

Bottom Line:
Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation.No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge.These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.

ABSTRACTAntigenic encounter generates long-term immunity sustained by long-lived high affinity plasma cells resident in the bone marrow (BM). Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos(-)(/)(-) mice with a range of hapten concentrations. Chimera reconstitutions demonstrate that the BM plasma cell defect is B cell intrinsic. Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation. No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge. These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.

fig3: Severe reduction in the total numbers of AFCs and Ab titers during primary and secondary immune responses in Aio−/− mice. (A) Kinetics of high affinity NP-specific IgG1-producing AFCs in the BM and spleen of immunized WT (○) and Aio−/− (•) mice. (B) Kinetics of NP-specific IgG1 serum Ab of high (top) or all (bottom) affinity of WT (•) or Aio−/− (○) mice at the indicated times. The relative titers of anti-NP Ab were measured by ELISA using either NP4 (top) or NP23 (bottom) as the coating Ag. Each point represents an individual mouse (day 7, n = 7; day 40, n = 4 for WT; n = 6 for Aio−/−; day 7 after 2°, n = 5 for WT and n = 7 for Aio−/−; day 13 after 2°, n = 3 for WT and n = 4 for Aio−/−; days 18 and 50 after 2°, n = 3) and data are from one of at least three representative studies. The arrows represent time of immunization.

Mentions:
To evaluate the overall ability of Aio−/− mice to mount a high affinity AFC response, the total number of AFCs (mostly obtained from BM and spleen) was examined. After the first encounter with Ag, the total number of high affinity NP-specific AFCs in Aio−/− mice was on average 10-fold lower than WT (Fig. 3 A, from day 14 to 120). After rechallenge with Ag, an increase was initially seen in the total number of high affinity AFCs in the Aio−/− mice, which was accounted for by the splenic compartment. This increase was short-lived, however, and by day 14 the difference in total AFCs between WT and Aio−/− mice increased to ninefold (Fig. 3 A). Thus, although memory B cells are produced in Aio−/− mice and upon recall can differentiate into short-lived high affinity splenic AFCs, they fail to generate the long-lived high affinity AFC population in the BM.

fig3: Severe reduction in the total numbers of AFCs and Ab titers during primary and secondary immune responses in Aio−/− mice. (A) Kinetics of high affinity NP-specific IgG1-producing AFCs in the BM and spleen of immunized WT (○) and Aio−/− (•) mice. (B) Kinetics of NP-specific IgG1 serum Ab of high (top) or all (bottom) affinity of WT (•) or Aio−/− (○) mice at the indicated times. The relative titers of anti-NP Ab were measured by ELISA using either NP4 (top) or NP23 (bottom) as the coating Ag. Each point represents an individual mouse (day 7, n = 7; day 40, n = 4 for WT; n = 6 for Aio−/−; day 7 after 2°, n = 5 for WT and n = 7 for Aio−/−; day 13 after 2°, n = 3 for WT and n = 4 for Aio−/−; days 18 and 50 after 2°, n = 3) and data are from one of at least three representative studies. The arrows represent time of immunization.

Mentions:
To evaluate the overall ability of Aio−/− mice to mount a high affinity AFC response, the total number of AFCs (mostly obtained from BM and spleen) was examined. After the first encounter with Ag, the total number of high affinity NP-specific AFCs in Aio−/− mice was on average 10-fold lower than WT (Fig. 3 A, from day 14 to 120). After rechallenge with Ag, an increase was initially seen in the total number of high affinity AFCs in the Aio−/− mice, which was accounted for by the splenic compartment. This increase was short-lived, however, and by day 14 the difference in total AFCs between WT and Aio−/− mice increased to ninefold (Fig. 3 A). Thus, although memory B cells are produced in Aio−/− mice and upon recall can differentiate into short-lived high affinity splenic AFCs, they fail to generate the long-lived high affinity AFC population in the BM.

Bottom Line:
Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation.No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge.These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.

ABSTRACTAntigenic encounter generates long-term immunity sustained by long-lived high affinity plasma cells resident in the bone marrow (BM). Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos(-)(/)(-) mice with a range of hapten concentrations. Chimera reconstitutions demonstrate that the BM plasma cell defect is B cell intrinsic. Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation. No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge. These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.